Men and male rats are predisposed to hypertensive renal injury compared to women or female rats. The mechanisms responsible for these gender differences are unclear; however, recent studies have strongly implicated androgens. The overall goal of this proposal is to investigate the mechanisms responsible for androgen-induced renal injury. We propose that the gender difference in renal injury is mediated by both hemodynamic and non-hemodynamic mechanisms. We hypothesize that the hemodynamic mechanism involves androgen-induced activation of the renin angiotensin II (Ang II) system (RAS), leading to increases in proximal sodium (Na) reabsorption, reduction of Na at the macula densa and decreases in afferent resistance. Non-hemodynamic mechanisms are mediated by Ang II stimulation of cytokines, growth factors and transcription factors to produce extracellular matrix. Ang II will also stimulate oxidative stress which further activates transcription factors and causes glomerular injury. In Aim 1 the hypothesis will be tested that androgens mediated via the androgen receptor are responsible for promoting glomerular injury in hypertensive male SHR, by increasing testosterone to promote injury, using androgen receptor antagonists to prevent injury , and triple therapy to determine the role of androgen-mediated increases in BP alone. In Aim 2 the hypothesis will be tested that androgens stimulate the RAS to increase Ang II which leads to increases in cytokines (such as TGF-B), extracellular matrix proteins, and transcription factors (AP- 1, NF-KB). The hypothesis will be tested in SHR and cyclically stretched mesangial cells (MSCs) (to mimic increased glomerular pressure) using biochemical, molecular and genetic array techniques to measure cytokines, extracellular matrix, activation of transcription factors with and without Ang II antagonists. In Aim 3, the hypothesis will be tested that Ang II will promote injury in males by producing oxidative stress and will be studied using SHR and stretched MSCs in the presence or absence of antioxidants and factors known to be activated by oxidative stress (superoxide, isoprostanes, heme oxygenase-1, peroxynitrite, etc) will be measured by biochemical assays.